CD47 targeted therapies for the treatment of infectious disease
Inventors
Weiskopf, Kipp Andrew • Hasenkrug, Kim J. • Stoddart, Cheryl A. • McCune, Joseph McCrary • Weissman, Irving L.
Assignees
University of California San Diego UCSD • Leland Stanford Junior University • US Department of Health and Human Services
Publication Number
US-11780931-B2
Publication Date
2023-10-10
Expiration Date
2034-02-05
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Abstract
Methods are provided for treating a subject with for an intracellular pathogen infection, by administering an agent that reduces the binding of CD47 on a infected cell to SIRPα on a host phagocytic cell, in an effective dose for increasing the phagocytosis of infected cells.
Core Innovation
The invention provides methods for treating a subject infected with an intracellular pathogen by administering an agent that reduces the binding of CD47 on infected cells to SIRPα on host phagocytic cells. The effective dose of this agent increases the phagocytosis of infected cells, thus promoting their removal by the immune system. Suitable agents include soluble high affinity SIRPα polypeptides, soluble CD47, anti-CD47 antibodies, and anti-SIRPα antibodies, which may be humanized or modified for different mammalian species.
The background identifies that healthy cells express CD47 as a “don't eat-me” signal that binds to SIRPα on phagocytes to inhibit their engulfment. Infectious agents can induce infected cells to upregulate CD47, thereby evading programmed cell death and phagocytic removal. This evasion contributes to persistent infections, and the invention addresses this problem by blocking the CD47-SIRPα interaction to restore phagocytic clearance of infected cells.
The methods are applicable to treating a broad range of intracellular infections, including chronic viral infections (such as retroviruses, lentiviruses, hepadna viruses, herpes viruses, and human papilloma viruses), intracellular bacterial infections (including Mycobacterium, Chlamydophila, Ehrlichia, and others), and intracellular protozoan pathogens (such as Plasmodium, Trypanosoma, Giardia, and Leishmania). The invention also encompasses in vivo and ex vivo targeting or depletion of infected cells using anti-CD47 agents, with the goal of increasing phagocytosis and reducing infectious disease burden.
Claims Coverage
The patent contains two independent claims directed to methods of treating human subjects infected with retroviruses or lentiviruses using anti-CD47 agents, focusing on increasing phagocytosis of infected cells and optionally combining with antiviral agents. The claims define specific types of anti-CD47 agents and treatment modalities.
Use of anti-CD47 agents to increase phagocytosis of virus-infected cells
Administering to a human subject infected with a retrovirus or lentivirus an anti-CD47 agent that reduces the binding of CD47 on infected cells to SIRPα on phagocytic cells, at an effective dose to increase phagocytosis. The anti-CD47 agent is selected from anti-CD47 antibodies, anti-SIRPα antibodies that do not stimulate signaling, SIRPα polypeptides that bind CD47, or soluble CD47 polypeptides that bind SIRPα without stimulating signaling.
Specific anti-CD47 agent types for treatment
Anti-CD47 antibodies can be fully human, humanized, or chimeric, including antibody fragments such as Fab, Fab', Fv, or diabodies. Anti-SIRPα antibodies do not stimulate SIRPα signaling but reduce CD47-SIRPα binding. SIRPα-derived polypeptides include those with modified d1 domains to increase affinity, possibly fused to immunoglobulin Fc regions. Soluble CD47 polypeptides bind SIRPα without activating signaling.
Combination therapy with antiviral agents
Treating a human subject infected with a retrovirus or lentivirus by administering (i) an anti-CD47 agent as defined above, and (ii) an antiviral agent. Applicable antiviral agents include cytokines like interferon γ, tumor necrosis factor α, interleukin 12, and drugs such as acyclovir and gancyclovir. The combination further increases phagocytosis of infected cells.
The claims cover methods of treating retroviral or lentiviral infections in humans by using specific anti-CD47 agents to inhibit CD47-SIRPα interactions, thereby enhancing phagocytosis of infected cells. These methods include the use of various anti-CD47 antibody types, engineered SIRPα polypeptides, and soluble CD47 proteins. Additionally, combinations with antiviral agents are claimed to improve treatment outcomes.
Stated Advantages
Increased phagocytosis of infected cells by blocking CD47-SIRPα interaction promotes removal of infected cells, potentially overcoming persistent infections.
The methods allow targeting of intracellular pathogens that evade immune clearance via CD47 upregulation, providing a new therapeutic approach.
Suitable for treating a broad range of intracellular infectious diseases including chronic viral, bacterial, and protozoan infections.
Documented Applications
Treating subjects infected with intracellular pathogens such as retroviruses, lentiviruses (including HIV-1, HIV-2, HTLV, FIV, and SIV), hepadna viruses, herpes viruses, human papilloma viruses, intracellular bacteria like Mycobacterium, Chlamydophila, Ehrlichia, and intracellular protozoan pathogens (e.g., Plasmodium, Trypanosoma, Giardia, Toxoplasma, and Leishmania).
Ex vivo depletion of infected cells from biological samples such as blood from infected subjects.
In vivo treatment of infectious diseases by systemic administration of anti-CD47 agents alone or combined with antiviral agents and cytokines.
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